PROJECT ABSTRACT Substance use disorders (SUDs) are estimated to cause over $400 billion worth of monetary damage to the US economy on an annual basis [1]. Recently, the misuse of heroin and prescription pain medications has become a major public health concern, The number of deaths related to overdose from either heroin or prescription pain medications has more than quadrupled over the last decade from approximately 16,000 in 2006 to more than 70,000 in 2017 [2]. With the rising overdose deaths and more than 3 million US citizens and more than 16 million citizens worldwide suffering from opioid use disorders (OUD), opioid overdose was declared a national emergency in the United States in 2017 [3]. CARI Therapeutics proposes to develop a continuous monitoring system based on an injectable biosensor, approximately the size of a grain of rice, implanted subcutaneously that detects and monitors substance use by products in the interstitial fluid. This continuous monitoring system not only has the potential to improve upon the current screening capabilities by detecting a higher number of at-risk patients, but the data it will provide doctors on substance use patterns over time will also enable them to more accurately diagnose the presence and severity of substance use disorders. Furthermore, it will allow health care providers to treat patients more effectively by giving them access to continuous monitoring data of their patients? prescription pain medication as well as street drug use. The current methods enable neither reliable substance use measurements over time nor detection of newer agents where screening tests are not available. There is a critical need to not only simplify data needed to detect substance use disorders, but to enable doctors to recommend or prescribe the appropriate treatment, followed by measuring adherence to the treatment, thereby making it more effective. In particular, there is a national opioid misuse epidemic with increasing overdose deaths [2], and the risk of overdose among users has become even greater with the introduction of highly potent synthetic opioids that require better detection methods than current urine drug screens [4]. A novel, minimally invasive, biosensor-based approach constitutes an innovative new way to detect substance use, monitor patients and inform treatment solutions. Currently no other commercially available solutions exist that can detect multiple substances and measure them continuously over time. In Phase I, we successfully built a minimally invasive opioid BioMote based on a non-enzymatic assay that is highly selective, sensitive, accurate, and stable in solution and serum and showed excellent catalytic response to two types of opioids: morphine and fentanyl. In Phase II, we will begin the FDA approval process (Aim 1), expand the lifetime and functionality of the biosensor to include detection of synthetic opioids (Aim 2), develop a reliable and safe deployment and extraction procedure (Aim 3), and validate the accuracy, safety, and reliability of the device in animal and human testing (Aim 4).